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Novel Stem Cell Model Uncovers Macrophage-Mediated Antiviral Immunity and Repair in Human Type 2 Alveolar Epithelial Cells

ABSTRACT: The lung alveoli are constantly exposed to inhaled pathogens and inorganic hazards, relying on robust defence mechanisms to maintain homeostasis. Alveolar macrophages and type 2 alveolar epithelial cells (AT2s) collaborate to orchestrate protection. Compromised defence can dysregulate immunity and repair, leading to acute and chronic respiratory diseases. To better understand these processes and drive therapeutic discovery, human model systems that capture key cell interactions are essential. Here, we develop the first induced pluripotent stem cell (iPSC)-derived platform that integrates AT2 cells and macrophages in an air-liquid interface. Coculture enhanced AT2-specific gene expression and lipid synthesis, while macrophages actively metabolised surfactant. iPSC-derived AT2s supported macrophage survival by producing M-CSF, promoting an alveolar macrophage-like phenotype. Additionally, macrophages played a crucial role in modulating proinflammatory signalling, enhancing antiviral immunity, and restricting viral replication during respiratory infections. Furthermore, we identify a role for iPSC-derived macrophages in epithelial repair, a process disrupted by VEGF signalling. We present an iPSC-derived platform to study AT2-macrophage interactions in homeostasis, infection, and repair, offering valuable insights into their roles in respiratory disease initiation and progression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE294640 | GEO | 2026/03/04

REPOSITORIES: GEO

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Project description:The coronavirus disease 2019 (COVID-19) pandemic has affected nearly 700 million and claimed more than 6 million lives. However, the large heterogeneity in disease susceptibility and severity of illness (SOI) remains poorly understood. A growing body of evidence suggests that alveolar epithelial cell type 2 (AT2), which constitute 10-15% of all alveolar cells and are critical for alveolar homeostasis, are the primary targets of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection and damage to AT2s may directly contribute to disease severity and poor prognosis in COVID-19 patients. Our in-vitro modeling of SARS-CoV-2 infection, in well-characterized, highly uniform, (r2 at 95% CI = 0.92 ± 0.03), induced pluripotent stem cell (iPSC) derived AT2s from 10 participants of our Mexican American Family Study, showed interindividual variability in infection susceptibility and the post-infection cellular viral load. To understand the underlying mechanism of the AT2’s capacity to regulate SARS-CoV-2 infection and cellular viral load, we performed a systematic characterization of the pre- and post-SARS-CoV-2 challenged AT2 transcriptomes. A total of 1,393 genes were found significantly (Oneway ANOVA FDR corrected p ≤ 0.05; FC abs ≥ 2.0) differentially expressed (DE) between pre- and post-SARS-CoV-2 infection-challenged AT2 and suggest significant upregulation of viral infection-related cellular innate immune response pathways (p-value ≤ 0.05; activation z-score ≥ 3.5), whilst the cholesterol and xenobiotic related metabolic pathways were significantly downregulated (p-value ≤ 0.05; activation z-score ≤ - 3.5). Interestingly, pre-infection expression of 238 DE genes showed a high correlation with the post-infection SARS-CoV-2 viral load (FDR corrected p-value ≤ 0.05, and r2-absolute ≥ 0.57). The 85 genes whose expression was negatively correlated with the viral load showed significant enrichment in viral recognition and cytokine-mediated innate immune GO biological processes (p-value range: 4.65x10-10 to 2.24x10-6). The 153 genes whose expression was positively correlated with the viral load showed significant enrichment in cholesterol homeostasis, extracellular matrix, and MAPK/ERK pathway-related GO biological processes (p-value range: 5.06x10-5 to 6.53x10-4). Overall, our results strongly suggest that AT2s pre-infection innate immunity and metabolic state affects their susceptibility to SARS-CoV-2 infection and viral load.

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Novel Stem Cell Model Uncovers Macrophage-Mediated Antiviral Immunity and Repair in Human Type 2 Alveolar Epithelial Cells

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